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1.
Anticancer Res ; 41(7): 3317-3326, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230127

RESUMO

BACKGROUND/AIM: We evaluated the impact of FosL1, a member of the activated protein-1 family, on the pathways leading to regional metastasis of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: We examined the influence of small interfering RNA (siRNA) and short heparin RNA (shRNA) mediated knockdown of FosL1 on cell migration, invasion, and proliferation in vitro as well as on regional metastasis in vivo. The prognostic significance of FosL1 was also analyzed using the Kaplan- Meier plotter using data from an HNSCC patient database. RESULTS: Down-regulation of FosL1 inhibited cell migration, invasion, and proliferation in vitro, decreased the incidence of regional metastases, and prolonged the survival of mice in vivo. We also determined that HNSCC patients with higher expression levels of FosL1 had a significantly shorter survival time than those with low expression of FosL1. CONCLUSION: FosL1 plays a crucial role in promoting cell migration, invasion, and proliferation in HNSCC.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Invasividade Neoplásica/genética , Proteínas Proto-Oncogênicas c-fos/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Animais , Linhagem Celular Tumoral , Regulação para Baixo/genética , Humanos , Metástase Linfática/genética , Metástase Linfática/patologia , Camundongos , Camundongos Nus , Invasividade Neoplásica/patologia , Prognóstico , RNA Interferente Pequeno/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
2.
Anticancer Res ; 41(7): 3349-3361, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230131

RESUMO

BACKGROUND/AIM: The present study investigated the oncogenic functions of TACC3 in the progression of gastric cancer (GC). MATERIALS AND METHODS: We analysed TACC3 in relation to cell growth, invasion capability, expression of epithelial-mesenchymal transition (EMT)-related markers, and ERK/Akt/cyclin D1 signaling factors. The correlation between the immunohistochemically confirmed expression of TACC3 and clinical factors was also analyzed. RESULTS: The increased proliferation and invasion of TACC3-over-expressing GC cells was accompanied by altered regulation of EMT-associated markers and activation of ERK/Akt/cyclin D1 signaling. Immunohistochemical analysis of TACC3 in human GC tissues revealed that its expression is correlated with aggressive characteristics and poor prognosis of intestinal-type GC. CONCLUSION: TACC3 contributes to gastric tumorigenesis by promoting EMT via the ERK/Akt/cyclin D1 signaling pathway. The correlation between TACC3 expression and multiple clinicopathological variables implies that its effective therapeutic targeting in GC will depend on the tumor subtype.


Assuntos
Carcinogênese/genética , Ciclina D1/genética , Transição Epitelial-Mesenquimal/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Gástricas/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Transdução de Sinais/genética , Estômago/patologia , Neoplasias Gástricas/patologia
3.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199510

RESUMO

During aggressive cancer progression, cancer cells adapt to unique microenvironments by withstanding various cellular stresses, including endoplasmic reticulum (ER) stress. However, the mechanism whereby cancer cells overcome the ER stress to survive remains to be elucidated. Herein, we demonstrated that microtubule acetylation in cancer cells grown on a stiff matrix promotes cancer progression by preventing excessive ER stress. Downregulation of microtubule acetylation using shRNA or CRSIPR/Cas9 techniques targeting ATAT1, which encodes α-tubulin N-acetyltransferase (αTAT1), resulted in the upregulation of ER stress markers, changes in ER morphology, and enhanced tunicamycin-induced UPR signaling in cancer cells. A set of genes involved in cancer progression, especially focal adhesion genes, were downregulated in both ATAT1-knockout and tunicamycin-treated cells, whereas ATAT1 overexpression restored the gene expression inhibited by tunicamycin. Finally, the expression of ATAT1 and ER stress marker genes were negatively correlated in various breast cancer types. Taken together, our results suggest that disruption of microtubule acetylation is a potent therapeutic tool for preventing breast cancer progression through the upregulation of ER stress. Moreover, ATAT1 and ER stress marker genes may be useful diagnostic markers in various breast cancer types.


Assuntos
Acetiltransferases/genética , Neoplasias da Mama/genética , Estresse do Retículo Endoplasmático/genética , Proteínas dos Microtúbulos/genética , Tunicamicina/farmacologia , Acetilação/efeitos dos fármacos , Acetiltransferases/antagonistas & inibidores , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas dos Microtúbulos/antagonistas & inibidores , Microtúbulos/efeitos dos fármacos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Microambiente Tumoral/efeitos dos fármacos
4.
Nat Commun ; 12(1): 4308, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262028

RESUMO

Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.


Assuntos
Neoplasias da Mama/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-11/metabolismo , Fator de Transcrição MafF/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Hipóxia Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator de Transcrição MafF/genética , Camundongos , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Proteínas Nucleares/genética , Prognóstico , Transdução de Sinais , Transcrição Genética
5.
Int J Mol Sci ; 22(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34281253

RESUMO

Radical cystectomy is the primary treatment for muscle-invasive bladder cancer; however, approximately 50% of patients develop metastatic disease within 2 years of diagnosis, which results in dismal prognosis. Therefore, systemic treatment is important to improve the prognosis of muscle-invasive bladder cancer. Currently, several guidelines recommend cisplatin-based neoadjuvant chemotherapy before radical cystectomy, and adjuvant chemotherapy is recommended in patients who have not received neoadjuvant chemotherapy. Immune checkpoint inhibitors have recently become the standard treatment option for metastatic urothelial carcinoma. Owing to their clinical benefits, several immune checkpoint inhibitors, with or without other agents (including other immunotherapy, cytotoxic chemotherapy, and emerging agents such as antibody drug conjugates), are being extensively investigated in perioperative settings. Several studies for perioperative immunotherapy have shown that immune checkpoint inhibitors have promising efficacy with relatively low toxicity, and have explored the predictive molecular biomarkers. Herein, we review the current evidence and discuss the future perspectives of perioperative systemic treatment for muscle-invasive bladder cancer.


Assuntos
Neoplasias da Bexiga Urinária/terapia , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/tendências , Cisplatino/uso terapêutico , Cistectomia , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/tendências , Invasividade Neoplásica/patologia , Assistência Perioperatória/métodos , Assistência Perioperatória/tendências , Período Perioperatório , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia
6.
Eur J Obstet Gynecol Reprod Biol ; 263: 181-191, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34218206

RESUMO

OBJECTIVE: To identify women with high-risk endometrial cancers using expert and non-expert transvaginal ultrasonography (TVS) and MRI. STUDY DESIGN: Myometrial involvement was prospectively evaluated in patients with atypical hyperplasia or endometrial cancer on ultrasound by non-experts at first visit (non-expert-TVS: n = 266) and experts (expert-TVS: n = 188) at second visit. MRI (n = 175) was performed when high-risk cancer was suspected on non-expert-TVS. Preoperatively, high-risk cancer was defined as myometrial involvement ≥50 %, or preoperative unfavorable tumor histology (grade 3 endometrioid, non-endometrioid tumors, or tumor in cervical biopsies) obtained by endometrial sampling or hysteroscopic biopsies. Preoperative evaluations were compared with final histopathology obtained at surgery, high-risk cancer being defined as unfavorable tumor histology or patients with FIGO stage ≥1b. RESULTS: Preoperative unfavorable tumor histology was seen in 64 women and correctly identified 63 of 128 high-risk cancers. Preoperative diagnosis of unfavorable tumor histology or myometrial involvement ≥50 %, i.e. judged high-risk, had an area under the curve (AUC), sensitivity, and specificity of 79.5 %, 93.8 %, 65.2 % on non-expert-TVS; 85.5 %, 84.4 %, 86.5 % on expert-TVS, and 85.4 %, 89.6 %, 81.2 % on MRI. AUC values were not significantly different between MRI and expert-TVS, but lower on non-expert-TVS (p < 0.02). However, sensitivity was highest on non-expert-TVS, where a low cutpoint for myometrial involvement was used (included potentially deep and difficult evaluations) in contrast to an exact cutpoint of myometrial involvement ≥50 % used on expert-TVS and MRI. The highest AUC, 88.6 %, was seen when MRI was performed in patients with myometrial involvement ≥50 %, determined on non-expert TVS. Sensitivity was reduced to 85.9 %, while specificity increased to 91.3 %. Thus, MRI was needed for risk classification in only 104 (39 %) patients. CONCLUSION: Diagnostically, expert-TVS and MRI were comparable and superior to non-expert-TVS. However, non-expert-TVS classified all patients with unclear myometrial involvement ≥50 %, and thereby only misdiagnosed 6.2 % of high-risk cases. Non-expert-TVS combined with MRI when myometrial involvement was ≥50 % on non-expert-TVS was a simple and effective method comparable with expert imaging to identify low- and high-risk cancer and select patients for SLND. Addition of MRI to the diagnostic regimen was needed in only 39 % of our patients.


Assuntos
Neoplasias do Endométrio , Imageamento por Ressonância Magnética , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Feminino , Humanos , Miométrio/diagnóstico por imagem , Miométrio/patologia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Sensibilidade e Especificidade , Ultrassonografia
7.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201897

RESUMO

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the "intestinal pathway", to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.


Assuntos
Carcinoma Ductal Pancreático/patologia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/classificação , Carcinoma Ductal Pancreático/genética , Cromograninas/genética , Progressão da Doença , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Camundongos , Modelos Biológicos , Mutação , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Intraductais Pancreáticas/classificação , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/genética , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética
8.
Clin Lab ; 67(7)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34258971

RESUMO

BACKGROUND: The aim of this study was to evaluate the accuracy of three combination staining approaches, each composed of pancytokeratin immunostaining with an elastic-fiber staining method of choice, in diagnosing visceral pleural invasion (VPI) in lung adenocarcinoma patients. METHODS: Tissue samples were resected from 23 lung adenocarcinoma patients, for whom neither hematoxylin and eosin nor Gomori's aldehyde-fuchsin (GAF) staining accurately detected the presence of VPI. Three slices were prepared from each sample and examined by immunohistochemical staining of cytokeratin AE1/AE3 and one of the following methods for elastic-fiber staining, including Victoria blue (VB), GAF, or Weigert's resorcin-fuchsin (WRF). The staining scores and slider view time were compared among the three staining protocols with tumor extension beyond the elastic layer of the visceral pleura as the diagnostic criterion for VPI. RESULTS: Conclusive diagnoses were achieved for all 23 tissue samples stained with VB, 18 with GAF, and 17 with WRF. VB staining was the fastest of the three methods, and produced significantly brighter, clearer color, and better contrast between the elastic fibers and tumor cells, thus facilitating slide review. CONCLUSIONS: The combination of VB elastic fiber and cytokeratin AE1/AE3 staining is a user-friendly, fast, and highly effective method that produces bright stains, favorable color contrast against the background, and high tumor localization accuracy. Hence, this method can improve the accuracy of VPI diagnosis and the corresponding staging of lung adenocarcinoma. We recommend the combined use of VB and pancytokeratin immunostaining when VPI is suspected.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/diagnóstico , Tecido Elástico/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Pleura/patologia , Prognóstico , Coloração e Rotulagem
9.
Medicine (Baltimore) ; 100(25): e26390, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160420

RESUMO

ABSTRACT: Hepatocellular carcinoma (HCC) involving the inferior vena cava rarely occurs, but its prognosis is extremely poor, with no established treatment to date. This study aimed to analyze the clinical outcome and toxicity of radiotherapy (RT) targeting inferior vena cava tumor thrombus (IVCTT) in HCC patients.From November 2011 to July 2020, medical record of 19 HCC patients who were treated with RT for IVCTT was retrospectively reviewed. RT was delivered using 3-dimensional conformal radiation therapy, intensity-modulated radiation therapy, and stereotactic body radiation therapy. The median radiation dose was 50 Gy (range, 45-55.8 Gy) for intensity-modulated radiation therapy and three-dimensional conformal radiotherapy. Stereotactic body radiation therapy was performed in 5 patients, for a total of 32 Gy in 4 fractions.The median follow-up duration was 8.1 months (range, 3.3-26.5 months). The median overall survival was 9.4 months (range, 3.7-26.5 months), and the 1-year overall survival rate was 37.1%. Eight of 19 patients (42.1%) had extrahepatic metastasis at the start of RT. Six of 11 patients (54.5%) who did not have extrahepatic metastasis at the start of RT showed extrahepatic metastasis after RT. The major cause of death was progression of extrahepatic metastasis (11 patients, 57.9%). The overall response rate of IVCTT for RT was 84.2%, and the local control rate at the time of the last follow-up was 89.4%. After RT, the most common first progression site was the lungs (9 patients, 47.4%). Most toxicities were grade 1 to 2 gastrointestinal (26.3%) and liver enzyme elevation (68.4%). Three patients occurred pulmonary embolism after RT later than 5 months after.RT is a feasible and safe local therapy for IVCTT, with favorable tumor control and acceptable toxicity. Extrahepatic metastasis is the major progression pattern and a leading cause of death in patients treated with RT. The combination of effective systemic therapy with RT may have to be considered.


Assuntos
Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Veia Cava Inferior/patologia , Trombose Venosa/radioterapia , Adulto , Idoso , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Progressão da Doença , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Prognóstico , Intervalo Livre de Progressão , Radiocirurgia/efeitos adversos , Dosagem Radioterapêutica , Radioterapia Conformacional/efeitos adversos , Radioterapia de Intensidade Modulada/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Veia Cava Inferior/diagnóstico por imagem , Trombose Venosa/diagnóstico , Trombose Venosa/etiologia , Trombose Venosa/patologia
10.
Aging (Albany NY) ; 13(13): 17901-17913, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34170850

RESUMO

BACKGROUND: Osteosarcoma (OS) is characterized by a high rate of metastasis. It has been found that tumor cells can bypass apoptosis which leads to an uncontrolled proliferation, but chloroquine (CQ) can have an effect on the tumors by inducing apoptosis. We aimed to explore the effects and the hypothetical mechanism of CQ effects on OS. METHODS: We first estimated the CQ effects on proliferation, apoptosis, migration, invasion, and lamellipodia formation of OS cells. Mice bearing xenograft model were used to test the anti-tumor growth and lung metastasis effects of CQ in OS. Western blot and immunohistochemistry were used to explore the mechanism of CQ effects and the association between p-STAT3 expression and lung metastasis of OS patients. RESULTS: CQ induces the apoptosis and suppressed the viability, proliferation, migration, invasion, and lamellipodia formation of OS cells in vitro. In vivo experiments demonstrated that CQ inhibited tumor growth and lung metastasis. CQ induced apoptosis was dependent on the lysosomal inhibition and inhibition of protein turnover. The lung metastasis was associated with the p-STAT3 expression in OS patients. CONCLUSION: CQ inhibited progression of OS cells in vitro, and suppressed tumor growth and lung metastasis in vivo. p-STAT3 can be a predictive biomarker for lung metastasis in osteosarcoma patients.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Proliferação de Células/efeitos dos fármacos , Cloroquina/farmacologia , Invasividade Neoplásica/patologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Fator de Transcrição STAT3/metabolismo , Adulto , Animais , Neoplasias Ósseas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/prevenção & controle , Osteossarcoma/metabolismo , Fosforilação , Pseudópodes/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
11.
J Obstet Gynaecol Res ; 47(9): 3331-3338, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34155730

RESUMO

AIM: The present study was designed to directly compare the diagnostic performance of preoperative magnetic resonance imaging (MRI) and intraoperative frozen section (FS) diagnoses in predicting deep myometrial invasion (MI) of endometrial cancer. METHODS: Using MRI findings and FS diagnoses, 194 patients with surgically staged endometrial cancer were evaluated for deep MI between 2006 and 2018. Definitive histological diagnosis of paraffin sections of excised tissues was used as the gold standard approach. RESULTS: Of 194 cases, 53 (27.3%) cases were finally diagnosed as having deep MI (≥50%). There was 82% total agreement between MRI and FS diagnoses in predicting deep MI, with a kappa value of 0.54 (95% confidence interval [CI] = 0.40-0.67, moderate agreement). The sensitivity of FS diagnosis (0.66, 95% CI = 0.52-0.78) for predicting deep MI was lower than that of MRI (0.77, 95% CI = 0.63-0.87; p = 0.21), while the specificity of FS (0.98, 95% CI = 0.93-0.99) was significantly higher than that of MRI (0.88, 95% CI = 0.81-0.93; p = 0.001). Overall, the accuracy of FS (0.89, 95% CI = 0.84-0.93) was higher than that of MRI (0.85, 95% CI = 0.79-0.90), although the difference did not reach statistical significance (p = 0.23). The accuracy (0.95, 95% CI = 0.90-0.97) was very high in cases with concordant MRI and FS results. CONCLUSIONS: MRI and FS showed different diagnostic characteristics for predicting deep MI, with a higher specificity observed for FS and the greatest accuracy obtained in concordant cases. Thus, our findings recommend the addition of FS diagnosis, either alone or in conjunction with MRI, to MI evaluation.


Assuntos
Neoplasias do Endométrio , Secções Congeladas , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Miométrio/diagnóstico por imagem , Miométrio/patologia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Sensibilidade e Especificidade
12.
Lung Cancer ; 158: 47-54, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34119932

RESUMO

OBJECTIVES: As a poor prognostic factor, visceral pleural invasion (VPI) was incorporated into non-small cell lung cancer (NSCLC) staging system. For modifying the T description of NSCLC, the prognostic value of VPI was assessed. MATERIALS AND METHODS: From 2010-2015, data on stage pT2N0M0 NSCLC patients with tumor size (TS) from 3.1 cm to 5.0 cm who received surgery from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled retrospectively. Propensity score matching was utilized to balance the baseline factors according to different TS intervals. Overall survival (OS) was assessed by the Kaplan-Meier method and log-rank test. Univariate and multivariate analysis were applied to identify the prognostic factors. The risk factors of VPI were calculated by logistic regression model. RESULT: The sum of 4005 resected stage pT2N0M0 NSCLC patients with TS from 3.1 cm to 5.0 cm were recruited, which had 1084 patients with VPI and 2921 patients without VPI respectively. As TS interval of 3.1-4.0 cm, the 5-year OS of patients without VPI was significantly better than those with VPI (62.6 % vs 58.7 %, P = 0.015), while the 5-year OS of patients with VPI and TS interval of 3.1-4.0 cm had no significant difference compared with patients whose TS interval of 4.1-5.0 cm (58.7 % vs 58.8 %, P = 0.918). Logistic regressive analysis manifested that older age, female, worse differentiation grade and larger TS had higher incidence of VPI (OR = 1.01, 1.25, 1.25, 1.16, respectively; P < 0.05 for all). CONCLUSION: This study underlined the prognostic effect of VPI and suggested that early-stage NSCLC with VPI and TS interval of 3.1-4.0 cm could be appropriately upstaged from pT2a (stage pIB) to pT2b (modified stage pIIA).


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
13.
Lung Cancer ; 158: 91-96, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34139640

RESUMO

OBJECTIVE: Lung cancer can spread in numerous ways, one of which has been suggested to be spread through air spaces (STAS). The tumor immune microenvironment appears to play a significant role in this spread. Particularly, tumor-associated macrophages (TAMs) can create a favorable microenvironment for tumor progression. In this study, we analyzed data from 709 patients with stage 0-IIIA lung adenocarcinoma, resected between 1999 and 2016, and investigated whether immune cell infiltration was associated with the occurrence of STAS and clinical outcome of the disease. MATERIALS AND METHODS: Tissue microarrays were constructed, and immunohistochemical analysis was performed for CD3, CD4, CD8, CD45RO, CD25, CD20, and CD68. The three tumor areas with the highest density of immune cells were photographed, and the immune cells were quantified. Associations between variables were analyzed using chi-square tests and Mann-Whitney U tests. Recurrence-free probability and overall survival were analyzed using log-rank tests and Cox proportional hazards models. RESULTS: After analyzing the associations between STAS and each type of immune cell infiltration, high density of CD68 + TAMs was identified as an independent predictor of a high STAS rate (p =  0.014) and was found to be associated with a high risk of recurrence, using univariate analysis (p =  0.008). After adjusting for CD68+ TAMs, pathological stage, and lymphovascular invasion, STAS remained significantly associated with a high risk of recurrence (HR = 3.50, p < 0.001). CONCLUSION: We demonstrated that a high density of CD68 + TAMs is an independent predictor of an increased STAS rate. Additionally, STAS is correlated with aggressive tumor behavior characteristics.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Humanos , Neoplasias Pulmonares/patologia , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral , Macrófagos Associados a Tumor
14.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065317

RESUMO

Lysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closely associated with poor clinical outcomes in ovarian cancer patients. In the present study, we determined a critical role and signaling cascade for the expression of DDR2 in LPA-induced ovarian cancer cell invasion. We also found ectopic expression of ATX or stimulation of ovarian cancer cells with LPA-induced DDR2 expression. However, the silencing of DDR2 expression significantly inhibited ATX- and LPA-induced ovarian cancer cell invasion. In addition, treatment of the cells with pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and mTOR abrogated LPA-induced DDR2 expression. Moreover, we observed that HIF-1α, located downstream of the mTOR, is implicated in LPA-induced DDR2 expression and ovarian cancer cell invasion. Finally, we provide evidence that LPA-induced HIF-1α expression mediates Twist1 expression to upregulate DDR2 expression. Collectively, the present study demonstrates that ATX, and thereby LPA, induces DDR2 expression through the activation of the PI3K/Akt/mTOR/HIF-1α/Twist1 signaling axes, aggravating ovarian cancer cell invasion.


Assuntos
Receptor com Domínio Discoidina 2/metabolismo , Lisofosfolipídeos/farmacologia , Neoplasias Ovarianas/induzido quimicamente , Neoplasias Ovarianas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Invasividade Neoplásica/patologia , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
15.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069970

RESUMO

Prostate cancer (PCa) is the second most leading cause of death in males. Our previous studies have demonstrated that δ-catenin plays an important role in prostate cancer progression. However, the molecular mechanism underlying the regulation of δ-catenin has not been fully explored yet. In the present study, we found that δ-catenin could induce phosphorylation of p21Waf and stabilize p21 in the cytoplasm, thus blocking its nuclear accumulation for the first time. We also found that δ-catenin could regulate the interaction between AKT and p21, leading to phosphorylation of p21 at Thr-145 residue. Finally, EGF was found to be a key factor upstream of AKT/δ-catenin/p21 for promoting proliferation and metastasis in prostate cancer. Our findings provide new insights into molecular controls of EGF and the development of potential therapeutics targeting δ-catenin to control prostate cancer progression.


Assuntos
Cateninas/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transporte Ativo do Núcleo Celular , Sítios de Ligação/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/química , Inibidor de Quinase Dependente de Ciclina p21/genética , Humanos , Ligantes , Masculino , Modelos Biológicos , Mutagênese Sítio-Dirigida , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Células PC-3 , Fosforilação , Neoplasias da Próstata/genética , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-akt/química , Transdução de Sinais , Treonina/química
16.
J Coll Physicians Surg Pak ; 30(6): 657-662, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34102776

RESUMO

OBJECTIVE: To identify additional staging information, venous, lymphatic, and neural invasion  as potential prognostic factors in colorectal cancer (CRC). STUDY DESIGN: A descriptive study. Place and Duration of the Study: University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey; from May 2007 to June 2019. METHODOLOGY: Retrospective analyses were performed on 855 CRC patients, who were treated with surgery. Patient and treatment characteristics, lymphovascular (LVI), and perineural (PNI) invasion were documented. The impact of LVI and PNI was determined using Cox proportional hazards model. RESULTS: The cohort examined had 346 (40.5%) LVI and 150 (17.5%) PNI positive patients. After surgery, mortality was 18.4% for LVI and 8% for PNI patients. Although increased ASA score (for ASA 2 hazard ratio [HR]=0.555, p=0.001 and ASA 3-4 HR=0.723, p=0.014), adjuvant chemotherapy (HR=2.5, p<0.001), LVI (HR=1.961, p<0.001) and PNI (HR=1.625, p<0.001) involvement increased the risk of death based on univariate analysis, multivariate Cox analysis showed a risk of death increase with increased ASA score (for ASA 2 HR=0.53, p<0.001 and ASA 3-4 HR=0.703, p=0.008), adjuvant chemotherapy (HR=2.114, p<0.001) and LVI involvement (HR=1.640, p<0.001). CONCLUSION: LVI and PNI may be useful in identifying CRC patients who might benefit the most from adjuvant systemic therapy. On the other hand, the presence of LVI and PNI reflects a shorter patient survival. Key Words: Lymphovascular invasion, Perineural invasion, Colorectal cancer, Cancer staging.


Assuntos
Neoplasias Colorretais , Neoplasias Colorretais/patologia , Humanos , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Turquia/epidemiologia
17.
Biochem Biophys Res Commun ; 559: 121-128, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33940382

RESUMO

Nucleolar protein 4-like (NOL4L) was first identified in acute myeloid leukaemia. Then, it was verified to be involved in cell progression in neuroblastoma. However, the functional role of NOL4L in tumor proliferation and metastasis and the underlying molecular mechanism(s) are not fully understood. Immunohistochemistry (IHC) assays were performed in patient tissues to reveal NOL4L expression profiles. Then, we knocked down NOL4L in two ovarian cancer cell lines (Skov3-ip1 and Hey), and cell-based in-vitro and in-vivo assays were subsequently conducted to gain insight into the underlying mechanism of NOL4L in ovarian cancer. We confirmed that the expression of NOL4L was higher in tumor tissues, especially in peritoneal metastatic tissues. Furthermore, we observed that NOL4L was related to prognosis in ovarian cancer patients. Next, we conducted CCK-8 assays, colony formation assays, migration and invasion experiments and wound healing assays and verified that NOL4L could promote proliferation and metastasis in ovarian cancer cells. In addition, NOL4L promoted tumor progression and metastasis in a nude mouse model. Mechanistically, we demonstrated that NOL4L influenced gene expression in the PI3K/AKT pathway. Overall, our study provides genetic and biochemical evidence that NOL4L is critical for tumor progression and metastasis in ovarian cancer cells. Thus, it could serve as a target for antimetastatic therapy in ovarian cancer.


Assuntos
Invasividade Neoplásica/patologia , Neoplasias Ovarianas/patologia , Proteínas/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
18.
Cancer Med ; 10(10): 3413-3426, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33932125

RESUMO

Metastasis to regional lymph nodes or distal organs predicts the progression of the disease and poor prognosis in esophageal squamous cell carcinoma (ESCC). Previous studies demonstrated that BTB and CNC homology 1 (BACH1) participates in various types of tumor metastasis. However, the function of BACH1 in ESCC was rarely reported. The present study demonstrated that BACH1 protein was overexpressed in ESCC tissues compared with paired esophageal epithelial tissues according to immunohistochemical staining (IHC). Higher levels of BACH1 mRNA were associated with decreased overall survival (OS) and shorter disease-free survival (DFS) of ESCC patients based on an analysis of The Cancer Genome Atlas (TCGA) datasets. BACH1 significantly enhanced the migration and invasion of ESCC in vitro. Mechanistically, BACH1 promoted the epithelial-mesenchymal transition (EMT) by directly activating the transcription of CDH2, SNAI2, and VIM, as determined by chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). BACH1 overexpression significantly enhanced CDH2 promoter activity according to the results of a luciferase assay. The results of subsequent experiments indicated that BACH1 enhanced the growth of tumor xenografts. The density of CD31+ blood vessels and the expression of vascular endothelial growth factor C (VEGFC) in tumor xenografts were significantly associated with BACH1 levels according to the results of IHC and immunofluorescence (IF) analyses performed in vivo. Moreover, ChIP-qPCR analysis demonstrated that the transcriptional activity of VEGFC was also upregulated by BACH1. Thus, BACH1 contributes to ESCC metastasis and tumorigenesis by partially facilitating the EMT and angiogenesis, and BACH1 may be a promising therapeutic target or molecular marker in ESCC.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Neovascularização Patológica/genética , Animais , Biomarcadores Tumorais/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Intervalo Livre de Doença , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Regiões Promotoras Genéticas/genética , Transcrição Genética/genética , Regulação para Cima/genética , Fator C de Crescimento do Endotélio Vascular/genética
19.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946266

RESUMO

Despite significant improvements in clinical management, pancreatic cancer (PC) remains one of the deadliest cancer types, as it is prone to late detection with extreme metastatic properties. The recent findings that pancreatic cancer stem cells (PaCSCs) contribute to the tumorigenesis, progression, and chemoresistance have offered significant insight into the cancer malignancy and development of precise therapies. However, the heterogeneity of cancer and signaling pathways that regulate PC have posed limitations in the effective targeting of the PaCSCs. In this regard, the role for K-RAS, TP53, Transforming Growth Factor-ß, hedgehog, Wnt and Notch and other signaling pathways in PC progression is well documented. In this review, we discuss the role of PaCSCs, the underlying molecular and signaling pathways that help promote pancreatic cancer development and metastasis with a specific focus on the regulation of PaCSCs. We also discuss the therapeutic approaches that target different PaCSCs, intricate mechanisms, and therapeutic opportunities to eliminate heterogeneous PaCSCs populations in pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Terapia de Alvo Molecular , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores Notch/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
20.
Head Neck ; 43(9): 2778-2785, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34050571

RESUMO

BACKGROUND: In this study, we aimed to investigate the relationships between histopathological and intraoral ultrasonographic (IUS) findings in patients with tongue cancer. METHODS: IUS and histopathological findings in 46 patients with tongue cancer were considered for this study. We assessed the relationships between IUS findings regarding tumor thickness, margin type, border type, and internal echo intensity; internal/peripheral Doppler findings; and muscle invasion and histopathological findings regarding tumor thickness, differentiation, Yamamoto-Kohama (YK)-classification grade, blood vessel invasion, lymphatic invasion, perineural invasion, and muscle invasion. RESULTS: Statistical associations were found between the following findings: between thickness determined through IUS measurement and that determined through histopathological measurement, between the IUS findings regarding tumor margin and border types and the histopathologically determined YK-classifications grades, and between a Doppler image of the internal area of tongue lesions and lymphatic invasion. CONCLUSIONS: IUS findings may be used to predict histopathological findings about tumor thickness and YK-classification grades.


Assuntos
Carcinoma de Células Escamosas , Neoplasias da Língua , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Humanos , Metástase Linfática , Margens de Excisão , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias da Língua/diagnóstico por imagem , Neoplasias da Língua/patologia , Ultrassonografia Doppler
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